INTRODUCTION — Discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) are variants of cutaneous lupus erythematosus (LE) that may occur independently or as manifestations of systemic lupus erythematosus (SLE). DLE most commonly occurs on the head and is characterized by well-defined, inflammatory plaques that evolve into atrophic, disfiguring scars (picture 1A-B). SCLE typically presents with erythematous, scaly papules or annular plaques on the neck, upper trunk, and arms (picture 2A-B). The symptomatic and disfiguring nature of DLE and SCLE underlies the need for appropriate treatment.

Most patients with DLE or SCLE will respond to conservative therapy with topical agents and antimalarial drugs; however, when the response to these interventions is inadequate, alternative immunomodulating or immunosuppressive drugs must be utilized. The management of patients with refractory DLE and SCLE will be discussed here; the initial management of these disorders and the clinical manifestations of DLE and SCLE are reviewed elsewhere. (See "Initial management of discoid lupus and subacute cutaneous lupus" and "Overview of cutaneous lupus erythematosus".)

APPROACH TO REFRACTORY DISEASE — For most patients with cutaneous lupus erythematosus (LE), strict photoprotection combined with topical or intralesional corticosteroids, topical calcineurin inhibitors, or systemic antimalarial agents results in satisfactory improvement. When disease is refractory to these interventions, other systemic agents are utilized. The adverse effects of many of these drugs limit their use to the subset of patients who fail to respond to conventional therapy.

Data on the efficacy of treatments for refractory discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) primarily are limited to small open-label studies, retrospective reviews, case series, and case reports. The scarcity of high-quality studies stems from a lack of pharmaceutical, governmental, and foundational support for large, multicenter, controlled trials in cutaneous LE, as well as the relative rarity of refractory cutaneous LE.

In addition, the historical absence of standardized objective measures of disease activity in cutaneous LE has made it difficult to systematically interpret the results of much of the published literature [1]. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was developed and validated as a tool to assess disease activity and skin damage in cutaneous LE [2,3]. The CLASI is now being used in a number of clinical trials and should improve the quality and applicability of data from studies of cutaneous LE [4]. A revised version of CLASI has also been proposed [5].

Choice of therapy — Patients with DLE or SCLE who have failed topical, intralesional, and antimalarial therapy can be treated with methotrexate, systemic retinoids, mycophenolate mofetil, or dapsone [6]. Among these agents, methotrexate and acitretin have the strongest evidence for efficacy for treatment of DLE and SCLE. In general, we favor methotrexate based upon the data supporting the use of this agent, as well as reports of patients in whom periods of disease remission occurred following the discontinuation of methotrexate therapy. Systemic retinoids (acitretin and isotretinoin) are much more expensive than methotrexate, and, in our experience, relapses occur quickly following discontinuation of these drugs. (See 'First-line agents' below.)

The ability of patients to tolerate treatments also influences the selection of the most appropriate medication. Methotrexate can cause serious toxicity in patients with renal insufficiency or pre-existing liver disease. Although methotrexate, mycophenolate mofetil, and systemic retinoids are all teratogenic, acitretin is an unfavorable choice for women of child-bearing potential due to the long period during which women must abstain from pregnancy following treatment with the drug (three years). Dapsone cannot be given to patients with sulfonamide allergies and must be used with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

When one or more of the above agents is unsuccessful, more aggressive therapy to induce disease remission should be considered. Thalidomide is highly effective for cutaneous LE, but it is the potential for serious adverse effects, including teratogenicity and a relatively high risk of peripheral neuropathy, that keeps thalidomide from being used as a first-line agent for refractory cutaneous LE. Thalidomide should only be used in patients who comprehend the risks associated with this drug. Intravenous immune globulin (IVIG) has also been effective as a remission-inducing agent, particularly for SCLE. Improvement following IVIG generally is short lived, and treatment with IVIG is expensive. (See 'Remission-inducing agents' below.)

A number of other treatments, such as azathioprine, rituximab, and other immunomodulatory agents, have also been used in refractory DLE and SCLE. However, the evidence for the efficacy of these drugs is limited and the range of adverse effects is wide, delegating the use of these agents to patients who fail to respond to the other therapies for refractory disease. Clofazimine has also been used for the treatment of refractory cutaneous LE, but the availability of this drug is limited. (See 'Other agents' below.)

Systemic glucocorticoids — Because of the chronic nature of cutaneous LE, the existence of only limited evidence for the efficacy of systemic glucocorticoids [7,8], and the numerous potential adverse effects of long-term therapy with systemic glucocorticoids, these drugs generally are not recommended for the treatment of DLE and SCLE [9].

FIRST-LINE AGENTS — Methotrexate, acitretin, isotretinoin, mycophenolate mofetil, and dapsone can be effective treatments for patients with discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) that is refractory to conventional therapy. (See 'Choice of therapy' above.)

Methotrexate — Methotrexate is a folic acid antagonist that has been used since the 1960s for systemic lupus erythematosus (SLE). The drug has also been shown to be effective for patients with cutaneous disease. Proposed mechanisms for the therapeutic properties of methotrexate in connective tissue diseases include anti-inflammatory effects secondary to increased production of adenosine, inhibitory action on lymphocytes and neutrophils, and suppression of antibody production [10-12].

Efficacy and administration — Treatment with methotrexate was beneficial for cutaneous LE in a six-month randomized trial in which 37 patients with SLE were treated with either methotrexate (15 to 20 mg/week) or placebo [13]. Compared with the patients who were given placebo, those who took methotrexate were less likely to have signs of active cutaneous LE (malar rash or DLE) at the end of the trial. The percentage of patients with cutaneous LE decreased from 60 to 16 percent in the group treated with methotrexate but increased from 76 to 84 percent in the placebo group. The authors did not distinguish between the response rates in patients with malar rash versus DLE.

The use of methotrexate specifically for refractory DLE and SCLE is supported by the results of retrospective studies and case reports [10,14-17]. In one retrospective study, 43 patients with cutaneous LE that was refractory to other systemic agents (including 16 subjects with SCLE and 12 subjects with DLE) were treated with 7.5 to 25 mg/week of oral or intravenous methotrexate [16]. All except one patient exhibited improvement in skin lesions, with the best clinical improvement noted in patients with SCLE or localized DLE. Another retrospective review of 12 patients with various types of cutaneous LE found similar success with methotrexate (10 to 25 mg/week) in refractory disease; complete or partial responses occurred in 9 out of the 10 patients with DLE or SCLE [17]. Five of the patients with cutaneous LE who responded to treatment also had long-lasting remissions after cessation of methotrexate therapy.

Typical doses of methotrexate for DLE or SCLE range from 10 to 25 mg per week. At the start of therapy, a test dose of 5 to 10 mg followed by a complete blood count and liver function tests five to six days later is given to assess patient tolerability to the drug [18]. Methotrexate can be administered orally, intramuscularly, subcutaneously, or intravenously.

Improvement with methotrexate is rapid, generally becoming evident within the first two to four weeks of therapy. Lesion clearance occurs at an average of six to eight weeks [16].

Adverse effects — Adverse effects of methotrexate include gastrointestinal upset, oral ulcers, bone marrow suppression, hepatotoxicity, pulmonary fibrosis, and renal toxicity. Daily folic acid supplementation may lessen the severity of gastrointestinal upset and oral ulceration [19].

Renal insufficiency increases the risk for toxicity, and the use of methotrexate should be carefully considered in older adult patients and those with renal disease. Dose adjustments are necessary when methotrexate is required in the setting of renal insufficiency. Alcohol abuse and pre-existing liver disease are additional relative contraindications for methotrexate therapy. Methotrexate is teratogenic and should be avoided in women for one to three cycles preceding pregnancy and in men for three months prior to an attempt to conceive. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)

Monitoring for hepatic, hematologic, and renal compromise before and during therapy is warranted in all patients treated with MTX. (See "Major side effects of low-dose methotrexate" and "Treatment of psoriasis in adults", section on 'Hepatotoxicity' and "Treatment of psoriasis in adults", section on 'Methotrexate' and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

Systemic retinoids — The systemic retinoids acitretin, isotretinoin, and etretinate can be effective for the treatment of DLE and SCLE [20-27]. Knowledge of the anti-inflammatory properties of retinoids and the beneficial effects of these drugs on epidermal keratinization prompted the use of these agents in cutaneous LE. Retinoids may be particularly useful in treating SCLE or hypertrophic forms of DLE [22,23,28,29].

Efficacy and administration — The aromatic retinoid etretinate was the first systemic retinoid studied for cutaneous LE. In an open-label study of 19 patients with cutaneous LE (including 11 patients with DLE and 7 patients with SCLE), 7 patients (64 percent) with DLE and 4 patients (57 percent) with SCLE obtained excellent or good responses to etretinate within two to six weeks of treatment [21]. The best responses were seen in males with DLE.

Etretinate was removed from the United States market in 1998 due concern over its prolonged elimination half-life (120 days). It was replaced by its metabolite acitretin, which was effective in treating cutaneous LE in a 12-week pilot study of 14 patients with DLE and 6 patients with SCLE. All patients with SCLE, and 9 out of the 14 patients with DLE, achieved complete clearing or marked reduction of lesions by the end of the study [22]. Seven patients who previously had not responded well to antimalarials or systemic glucocorticoids were among the responders to acitretin.

Acitretin (50 mg/day) was subsequently compared with hydroxychloroquine (400 mg/day) in an eight-week randomized trial of 58 patients with DLE or SCLE and was determined to have similar efficacy as hydroxychloroquine. Complete clearing or marked improvement occurred in 46 percent of patients treated with acitretin and 50 percent of patients treated with hydroxychloroquine [25]. Seven patients who had previously failed antimalarial therapy were included in the acitretin group (n = 28); however, the authors did not report response rates specific for this group. Adverse effects were more frequent with acitretin therapy.

Isotretinoin has a shorter elimination half-life than acitretin and etretinate, and favorable responses have been documented in patients with DLE and SCLE in an open-label study and case reports [24,26,27]. In the open-label study, 8 out of 10 patients with SCLE or DLE that was refractory to sunscreens, topical corticosteroids, and antimalarials completed a 16-week course of isotretinoin therapy (80 mg/day) [24]. All eight patients achieved a response designated as excellent. Two patients were lost to follow-up prior to the first two-week follow-up visit.

When used in the treatment of DLE, acitretin and isotretinoin usually are prescribed in doses of 0.2 to 1 mg/kg/day [6]. The response to retinoid therapy usually is rapid, occurring within the first two to six weeks of treatment [21,22,26]. However, our clinical experiences and that of others indicate that relapses often occur quickly once the drug is stopped [26].

Improvement in DLE and SCLE with oral alitretinoin (30 mg per day) has been reported in a few patients who failed treatment with a variety of other therapies [30]. Further study is necessary to evaluate the efficacy and safety of alitretinoin when used for cutaneous LE. Oral alitretinoin is not commercially available in the United States.

Adverse effects — The most common side effects of isotretinoin and acitretin include hypertriglyceridemia and xerosis, both of which resolve with drug discontinuation. Elevated transaminases, skeletal hyperostosis, and, rarely, leukopenia may also occur with systemic retinoids.

Retinoids are potent teratogens and must be used with caution in females of child-bearing age. Although acitretin has a shorter half-life than etretinate (two days), it can be reversely metabolized to etretinate, thereby prolonging the risk for teratogenicity. Due to its short elimination half-life, isotretinoin is a better choice for female patients of child-bearing potential; strict contraceptive practices must be adhered to during and for one month after cessation of isotretinoin. Three years of strict pregnancy prevention is necessary following the cessation of acitretin therapy. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Adverse effects'.)

Mycophenolate mofetil — Mycophenolate mofetil (MMF) is an immunosuppressant that reversibly inhibits inosine monophosphate dehydrogenase, an enzyme necessary for de novo purine synthesis. Because it preferentially targets cells that are dependent on de novo purine synthesis for DNA and RNA production, such as B and T cells, it has a more favorable toxicity profile than many other immunosuppressants.

Efficacy and administration — Evidence supporting the use of MMF for SCLE and DLE is limited to an open-label study [31], a retrospective study, and case reports [32-36]. In the open-label study, 10 patients with SCLE that was refractory to topical corticosteroids or antimalarials were treated with MMF (1440 mg/day) for three months [31]. Reductions in disease activity were statistically significant (Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] decreased from 10.8±6 to 2.9±2.6) [31]. In the retrospective study, the addition of MMF to existing treatment regimens led to at least partial disease improvement in all of 24 women with cutaneous LE refractory to antimalarial therapy who were treated with MMF for at least three months (19 with DLE, 3 with SCLE, 1 with DLE/SCLE overlap, and 1 with tumid LE) [37]. Final doses ranged from 1500 to 3500 mg/day (average final dose 2750 mg/day), and the mean time to initial treatment response was 2.76 months.

In contrast, a retrospective study of seven patients with a variety of skin manifestations of SLE (including three patients with DLE and one patient with SCLE) who failed to improve with or tolerate other systemic therapies found that MMF (2000 to 3000 mg/day) was poorly effective in treating skin disease; five out of seven patients did not respond to treatment [38]. One of the two patients who had a partial response to treatment was a patient with DLE who responded initially but subsequently experienced a disease flare during treatment. The other responder was a patient with urticarial vasculitis.

MMF typically is given in doses of 1 to 3 grams per day [6].

Adverse effects — Although mycophenolate mofetil is generally well tolerated, nausea, vomiting, and diarrhea are the most common adverse reactions. Administering the drug in two or three divided doses during the day may help to minimize gastrointestinal symptoms. Reversible cytopenias and teratogenicity are additional side effects of MMF. An increased risk of malignancy has been postulated but has not been definitively demonstrated to date. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Dapsone — Dapsone has variable efficacy in the treatment of DLE and SCLE. Like other sulfonamide drugs, its antimicrobial action occurs via inhibition of the folic acid pathway. The mechanisms underlying its anti-inflammatory properties are less clear, but the efficacy of dapsone in cutaneous disease primarily has been linked to inhibitory effects on neutrophil-mediated tissue damage and neutrophil migration. Concordantly, in clinical practice, dapsone has been most useful in treating skin conditions characterized by prominent neutrophilic infiltrates.

Efficacy and administration — Dapsone therapy can result in dramatic improvement in patients with bullous LE, a variant of cutaneous LE that presents with neutrophilic infiltrates on biopsy [39-41]. Although neutrophils are not a prominent feature in the histopathology of DLE and SCLE, dapsone is effective for some patients.

Evidence for the efficacy of dapsone in the treatment of SCLE is limited to case reports [42-46], but successful use of dapsone in DLE has been documented in a pilot study and retrospective review. In the pilot study, 16 patients with DLE were given dapsone (100 mg/day) for 6 to 16 weeks [47]. At the end of the study, four patients (25 percent) were noted to have appreciable improvement in skin disease; moderate improvement occurred in an additional four patients. A separate review of the records of 33 patients with DLE who were treated with dapsone revealed excellent improvement in eight patients (24 percent) and partial effect in another eight subjects [48]. The excellent responders included two out of six patients who were treated simultaneously with dapsone and hydroxychloroquine.

Therapeutic doses of dapsone range from 25 to 200 mg daily. Treatment is initiated with low doses, and the dose is gradually increased while closely monitoring hematologic parameters [10].

Adverse effects — Adverse effects of dapsone include hemolysis and methemoglobinemia. All patients develop some degree of hemolysis, but those with glucose-6-phosphate dehydrogenase (G6PD) deficiency are more likely to develop substantial hemolysis. Methemoglobinemia is dose dependent and is independent of G6PD status.

Idiosyncratic adverse reactions to dapsone include peripheral neuropathy, agranulocytosis, and dapsone hypersensitivity syndrome. Agranulocytosis may occur as early as three weeks into therapy and almost always occurs within the first 12 weeks of treatment [49]. Patients may present with fevers, pharyngitis, or, less commonly, signs of sepsis [50]. Fever, a morbilliform skin eruption, and hepatitis are features of the hypersensitivity syndrome. (See "Drug eruptions", section on 'Drug reaction with eosinophilia and systemic symptoms'.)

REMISSION-INDUCING AGENTS — For patients who fail treatment with one or more of the agents reviewed above, thalidomide or intravenous immune globulin (IVIG) can be used in an attempt to attain disease control. The potential adverse effects of these drugs make them most useful as short-term, remission-inducing agents, which can be followed by maintenance treatment with conventional therapies or other systemic medications for refractory cutaneous lupus erythematosus (LE). (See "Initial management of discoid lupus and subacute cutaneous lupus".)

Thalidomide — First synthesized as a sedative agent in 1954, thalidomide has had a tumultuous history. After the first description in 1961 of its association with phocomelia in infants born to mothers who had taken the drug during pregnancy, it was withdrawn from the pharmaceutical market worldwide in 1962. Despite these potential adverse effects, thalidomide can be highly effective for discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE).

The mechanism of action of thalidomide in cutaneous LE is incompletely understood but is thought to involve the inhibition of tumor necrosis factor (TNF)-alpha and the suppression of ultraviolet B (UVB)-induced keratinocyte apoptosis [51]. The detection of elevated levels of TNF-alpha in lesions of SCLE supports the theory that suppression of TNF-alpha is at least partially responsible for the efficacy of thalidomide for cutaneous LE [52]. However, drugs that inhibit TNF-alpha have also been implicated in the induction of lupus-like cutaneous and systemic disease. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Autoimmune diseases' and "Drug-induced lupus".)

Other potential mechanisms of action of thalidomide include modulation of lymphocyte proliferation, cytokine production, neutrophil chemotaxis, and angiogenesis [53].

Efficacy and administration — There are no randomized trials of thalidomide for DLE or SCLE. However, available data suggest thalidomide can be highly effective. A systematic review and meta-analysis of observational studies evaluating the efficacy of thalidomide for cutaneous LE found an overall rate of complete or partial response to thalidomide of 90 percent (95% CI 85-94), with similar response rates between cutaneous LE subtypes [54]. The pooled rate of complete response was 64 percent (95% CI 55-73).

Thalidomide has a quick onset of action; responses to thalidomide generally begin within the first month of treatment [55]. Thalidomide should be initiated at doses of 50 to 100 mg/day, and the dose should be tapered to the lowest effective dose after clinical improvement is attained [53].

Although the development of adverse effects, particularly peripheral neuropathy, limits long-term treatment with thalidomide in many patients, relapse often occurs within three to four months if therapy is discontinued [53-55]. Thus, thalidomide is frequently used as a therapeutic bridge while awaiting the onset of action of other systemic agents. In patients who tolerate thalidomide and cannot be transitioned to other effective therapies, thalidomide (25 to 50 mg/day or less) can be given as maintenance therapy [53]. In our clinical experience, some patients can maintain improvement on doses as low as 25 or 50 mg every three days. These patients should be monitored closely for adverse effects. (See 'Adverse effects' below.)

Adverse effects — Careful patient selection and conscientious monitoring must occur with the use of thalidomide. The most well-known and most serious toxicity of thalidomide is teratogenicity [53]. In the United States, thalidomide can only be prescribed through a Risk Evaluation and Mitigation Strategy (REMS) program (www.thalomidrems.com), a registration and monitoring program for the safe use of thalidomide [56]. Peripheral neuropathy and thromboembolic events are additional well-recognized serious complications of thalidomide. In the systematic review and meta-analysis, the pooled rates of peripheral neuropathy and thromboembolic events were 16 percent (95% CI 9-25) and 2 percent (95% CI 1-3), respectively [54]. The pooled rate of thalidomide withdrawal related to adverse effects was 24 percent (95% CI 14-35).

A retrospective, observational study evaluating all patients with histologically confirmed cutaneous LE treated with thalidomide in five dermatology departments of French university hospitals from 1992 to 2017 revealed an overall thrombosis risk of 2.74 for 100 patient-years and a risk for arterial thrombosis and venous thrombosis of 1.72 and 1.03 for 100 patient-years, respectively [57]. The risk for all thromboembolic events was higher for patients with a history of arterial thrombosis and hypercholesterolemia and was lower for patients with a starting thalidomide dose of less than or equal to 50 mg per day and for those who received concomitant hydroxychloroquine.

Sensory neuropathy typically precedes motor neuropathy. It is unclear whether the risk for this side effect is dose dependent [58-60]. If symptoms of neuropathy develop, the dose of thalidomide should be decreased [53]. If symptoms persist one month after dose reduction, thalidomide should be discontinued.

Guidelines in the REMS recommend that nerve conduction studies should also be performed at baseline and every six months thereafter. However, since symptoms of neuropathy may occur in patients with normal nerve conduction studies, this test should be used only as an adjunct to clinical assessment [53].

Treatment with thalidomide should be considered carefully in patients with other risk factors for venous thrombosis. (See "Overview of the causes of venous thrombosis" and "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)

Other side effects of thalidomide include sedation, constipation, endocrine dysfunction, and neutropenia.

Lenalidomide — Lenalidomide is a thalidomide derivative that is a far more potent inhibitor of TNF-alpha. This drug has a lower frequency of sedation, constipation, and neuropathy than thalidomide.

Beneficial effects of lenalidomide in refractory cutaneous LE have been reported [61-65]. In an open-label study in which 15 women with refractory cutaneous lupus (including 9 with DLE and 2 with SCLE) were treated with lenalidomide (initially 5 mg per day and increased to 10 mg per day if no improvement), 12 patients achieved complete responses (Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] score = 0), including 4 who previously failed thalidomide [63]. The remaining patients included two patients with DLE who achieved only partial improvement (at least 50 percent improvement in CLASI score [CLASI-50]) and one patient with DLE who was withdrawn from the study due to poor gastrointestinal tolerance of the drug. The patients with DLE and SCLE who achieved complete responses did so within a mean of six weeks (range 2 to 12 weeks), and the median length of treatment for all patients was 11 months. Relapses were common after the tapering or cessation of therapy.

In a smaller, six-week, open-label study, at least a four-point reduction in CLASI score occurred in four of five patients (three with DLE and one with a mixed presentation of SCLE and tumid LE) who were treated with lenalidomide (5 mg per day), including two who had previously failed thalidomide therapy [62]. Of note, one of the responders with DLE developed symptoms of systemic lupus erythematosus (SLE) during treatment, an event that the authors postulated may have been a side effect of lenalidomide therapy. However, none of the patients in the larger, open-label study experienced a similar event [63]. Additional studies are necessary to determine the role of lenalidomide in the treatment of cutaneous LE.

In a multicenter, retrospective case series evaluating 40 patients with cutaneous LE who received lenalidomide after failure of hydroxychloroquine and at least one second-line systemic treatment, lenalidomide therapy was associated with a 20 percent reduction in CLASI activity score (CLASI-20) in 98 percent of patients, CLASI-50 in 88 percent of patients, and a complete response (CLASI activity score of 0) in 43 percent of patients [64]. The complete response rate was decreased in active smokers.

In a retrospective review of 19 patients with cutaneous LE who had failed a median of six prior therapeutic agents, treatment with lenalidomide 5 mg/day resulted in an overall response rate of 89.5 percent (complete/nearly complete response in 12 out of 19 patients and a partial response in 5 out of 19 patients). Adverse events and serious adverse events occurred in 12 and 5 of the 19 patients, respectively [65].

Intravenous immune globulin — Intravenous immune globulin (IVIG) is a product derived from the pooled plasma of tens of thousands of donors that provides a vast array of immunoregulatory substances. The exact mechanisms of action of IVIG in the treatment of autoimmune disorders remain unknown. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Suppression of inflammatory/autoimmune processes'.)

Efficacy and administration — Data are limited on the use of IVIG for DLE and SCLE. The efficacy of IVIG was evaluated in an uncontrolled study of 12 patients with cutaneous LE that was refractory to other systemic therapies (including five patients with disseminated DLE and five patients with SCLE) [66]. Subjects were given a total of two doses of 1 g/kg of IVIG on consecutive days followed by 400 mg/kg monthly for up to six months. After treatment, five patients (42 percent) had more than 75 percent improvement in skin lesions, and two patients (17 percent) exhibited partial responses (50 to 75 percent improvement in skin lesions). Overall, patients with SCLE exhibited greater degrees of improvement than those with DLE, and relapse was common after the discontinuation of therapy. Several case reports have also supported the efficacy of IVIG for SCLE and DLE that had been refractory to other therapies [67-70].

In contrast, in a 12-month open-label study of IVIG in seven patients with cutaneous LE (including five patients with SLE manifesting as malar rash and oral ulcers and two patients with SCLE), monthly infusions of IVIG at a dose of 300 mg/kg/day for five days were associated with no change in disease activity in the patients with SLE and worsening of disease in those with SCLE [71].

Dosing regimens for IVIG vary, although it is often administered at a dose of 2 g/kg every four to eight weeks depending upon response [67,69]. Although responses are prompt, they are typically short lived, necessitating repeated infusions to maintain benefit. Some patients may fail to respond to subsequent courses of therapy after relapse [66].

Because of the high cost of this agent and high likelihood for relapse, it should be reserved for attempting to gain rapid control of severe, refractory disease while initiating other long-term therapies.

Adverse effects — Adverse events following IVIG infusion include hypersensitivity reactions, headache, vasculitis, aseptic meningitis, renal failure, myocardial infarction, and thrombosis. (See "Intravenous immune globulin: Adverse effects".)

OTHER AGENTS — Multiple other medications have been used for subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE).

Azathioprine — Successful treatment of DLE and SCLE with azathioprine has been reported. In an open-label study, four patients with refractory SCLE and two patients with refractory DLE were treated with azathioprine (100 to 150 mg/day) and prednisone (20 to 30 mg/day) [72]. One patient with SCLE had an excellent response with near clearing of skin lesions and a decreased oral prednisone requirement; two additional patients with SCLE exhibited partial responses. Adverse effects led to the discontinuation of therapy in two patients, and one patient with severe, erosive palmar DLE failed to respond to therapy. However, several case reports have supported the use of azathioprine in patients with extensive or recalcitrant DLE [73-75]. Improvement with azathioprine usually occurs within one to two months [10].

Adverse effects of azathioprine include bone marrow suppression [76], gastrointestinal upset [77-79], hepatitis, and abnormal liver function tests [76,80]. The risk of myelosuppression may be related to thiopurine methyltransferase (TPMT) activity, an enzyme involved in the metabolism of azathioprine. Assessment of the TPMT enzyme activity should be performed prior to initiating azathioprine therapy [81]. Most patients with cutaneous LE and normal TPMT activity are treated with 1 to 2.5 mg/kg/day of azathioprine. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

An increased incidence of lymphoproliferative malignancies has been reported in patients with rheumatoid arthritis treated with azathioprine [82,83]; however, it has not been proven that a similar risk occurs in patients treated with azathioprine for cutaneous LE. One retrospective study (n = 358) that compared the incidence of lymphoma in patients with SLE who were treated with azathioprine versus those who had not received the drug found no significant difference in the risk for lymphoma or other malignancies between the two groups [84].

Rituximab — Originally approved in 1997 for the treatment of non-Hodgkin's lymphoma, rituximab is a chimeric monoclonal antibody specific for human CD20, a membrane-associated glycoprotein highly expressed on the surface of pre-B cells and resting and activated mature B lymphocytes [85]. The binding of rituximab to CD20 results in B cell death [85].

Although a few case reports document improvement in severe, refractory SCLE with rituximab therapy [86-89], other data suggest poor efficacy for DLE and variable efficacy for SCLE. In a prospective uncontrolled study of 82 patients with SLE, none of eight patients with chronic cutaneous LE (DLE or chilblains) at baseline and one of two patients with SCLE at baseline responded to rituximab (1 g twice daily on days 1 and 15) [90]. In addition, nine patients who lacked skin disease or had acute cutaneous LE at baseline experienced flares of chronic cutaneous LE or SCLE after rituximab therapy. In a separate study of 17 patients treated with a rituximab-based B cell depleting regimen (two 1 g doses of rituximab separated by two weeks and 750 mg of cyclophosphamide given one day after the first rituximab infusion) for SLE and/or cutaneous LE, only three of eight patients with chronic cutaneous LE were in complete or partial remission six months after treatment [91]. The same endpoint was achieved by two of three patients with SCLE.

Although generally well tolerated, the adverse effects of rituximab include infections, nausea, serum sickness-like reactions [92], and infusion-related events including hypotension, fevers, and rigors. A boxed warning has been mandated by the US Food and Drug Administration (FDA) due to reports of fatalities from infusion reactions, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy due to JC virus in patients treated with rituximab.

Rituximab should be considered only for patients with severe, extensive, cutaneous LE that has failed to respond to other therapies for refractory disease.

Cyclosporine — Cyclosporine exerts its immunosuppressive effects via the inhibition of interleukin (IL)-2 and other cytokines. Combination therapy with cyclosporine and hydroxychloroquine was effective in improving skin lesions in a patient with SCLE and generalized lichen planus [93]. However, in other reports, cyclosporine failed to induce improvement in patients with DLE that was refractory to other therapies [94,95]. DLE has also occurred during treatment with cyclosporine for other disorders in patients without a history of cutaneous LE [96,97]. (See "Pharmacology of cyclosporine and tacrolimus".)

Belimumab — Belimumab is a monoclonal antibody that reduces B lymphocyte survival by blocking the binding of soluble human B lymphocyte stimulator to its B cell receptors. It is used for treatment of SLE. The effect of belimumab in cutaneous LE has not been well studied; however, in a series of five patients with SLE and acute cutaneous lupus erythematosus, SCLE, and/or DLE, all had significant improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) disease activity scores with the addition of intravenous belimumab to standard treatment [98]. The average time to clinical improvement was four months, and marked improvement occurred as early as eight weeks.

In a multicenter, retrospective, observational study of patients with cutaneous LE that was refractory to hydroxychloroquine and at least two second-line agents, treatment with belimumab 10 mg/kg every two weeks for three doses and then monthly resulted in 50 percent improvement in CLASI activity score (CLASI-50) in 8 of 16 patients and a complete response in 3 of 16 patients [99]. CLASI-50 was observed more frequently in patients with Fitzpatrick skin phototypes IV to VI than II or III (table 1), and baseline CLASI tended to be lower in patients with complete response than without.

Serious potential adverse effects of belimumab include hypersensitivity reactions, infections, and depression. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy'.)

Additional therapies — Other therapies that have been used in the treatment of cutaneous LE include ustekinumab [100,101], phenytoin [102], sulfasalazine [103-105], cefuroxime axetil [106], danazol [107,108], and extracorporeal photophoresis [109-111]. Despite reports of efficacy in cutaneous LE, phenytoin and sulfasalazine also have been associated with the development of drug-induced lupus. (See "Drug-induced lupus".)

Use of a novel tacrolimus 0.3% lotion was associated with reduced disease severity and hair regrowth in three patients with refractory DLE [112]. Tacrolimus 0.3% lotion is not commercially available.

Methyl aminolevulinic acid-photodynamic therapy (MAL-PDT) appeared effective for DLE in two case reports that described patients who failed or could not tolerate other therapies [113,114]. However, 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) was not useful in two patients with refractory DLE in another report [115].

INVESTIGATIONAL THERAPY — Examples of agents under investigation for their efficacy and safety in cutaneous lupus erythematosus (LE) include Janus kinase (JAK) inhibitors [116-118], anifrolumab (a humanized immunoglobulin G1 [IgG1] monoclonal antibody that binds interferon [IFN] alpha/beta/omega receptors and prevents type 1 IFN signaling) [119,120], and B11B059, a humanized IgG1 monoclonal antibody that binds dendritic cell antigen 2, a plasmacytoid dendritic cell-specific receptor that inhibits type 1 IFN production when ligated [121]. Although early findings suggest that these agents may have benefit in cutaneous lupus, further evaluation is necessary to explore the efficacy and safety of these treatments for cutaneous LE.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous lupus erythematosus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Discoid lupus (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Most patients with discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) respond well to treatment with photoprotection, topical medications, and systemic antimalarial drugs. Patients who fail to respond to these agents can be treated with alternative systemic therapies. These drugs have a wide range of potential adverse effects and should be prescribed with caution. (See 'Approach to refractory disease' above.)

●The decision of which agent to use for the treatment of refractory cutaneous lupus erythematosus (LE) should be based upon drug efficacy, assessment of the patient's comorbidities, and consideration of the drug's potential adverse effects. For some patients, cost may also be a factor. (See 'Choice of therapy' above.)

●For patients with DLE and SCLE who fail treatment with conventional therapy, we suggest treatment with methotrexate before other systemic agents for refractory disease (Grade 2C). Methotrexate has been shown to be efficacious for refractory cutaneous LE, can be used for long-term therapy, and is relatively inexpensive. For patients who cannot tolerate methotrexate, or do not respond to this drug, additional treatment options include systemic retinoids, mycophenolate mofetil, and dapsone. (See 'First-line agents' above.)

●Both methotrexate and systemic retinoids are categorized as pregnancy class X drugs, and women must abstain from pregnancy for three years following treatment with acitretin. In general, acitretin should be avoided in women of child-bearing potential. (See 'Adverse effects' above and 'Adverse effects' above.)

●Some patients fail to improve with first-line therapies for refractory cutaneous LE and may require more aggressive therapies to induce remission. For patients who fail to improve with first-line therapies for refractory cutaneous LE, we suggest treatment with thalidomide (Grade 2C). Intravenous immune globulin (IVIG) is another therapeutic option for inducing remission in patients with refractory cutaneous LE. (See 'Remission-inducing agents' above.)

●Patients treated with thalidomide should be well informed of the potential adverse effects of the drug and should be willing to comply with recommendations to ensure the safe use of thalidomide. Thalidomide is a potent teratogen, and, in the United States, both clinicians and patients must register in a Risk Evaluation and Mitigation Strategy (REMS) program prior to the initiation of therapy. Patients treated with the drug also should be monitored closely for the development of peripheral neuropathy. (See 'Thalidomide' above.)